Linear blocker polymer

ABSTRACT

Linear block polymer according to Formula (1) wherein R1 is derived from a diamine, e.g. ethylene diamine, 1,2-diamino propane or 1,3-diamino propane; R2 is derived from an aromatic diisocyanate; R3 is derived from an esterdiol; R4 is derived from dibutyl amine or ethanolamine; Where 08, wherein the monomers from which R2 and R3 are derived from are added in such amounts that the molar ratio between R2 and R3 is larger than 2:1.

TECHNICAL FIELD

The invention relates to a linear block polymer, to various preparationsmade from said linear block polymer, and to an implant comprising thelinear block polymer.

BACKGROUND ART

Certain injuries to soft tissue of the body do not heal by itself. Oneexample of such an injury is injuries to the meniscus, injuries commonto certain athletes. When such an injury happened, the injured part wasoften removed, resulting in reduced bodily functions. This often meantthe end of the career of the athlete. A continued high load on a kneewithout a meniscus leads to wear of the skeleton on the bearingsurfaces, with permanent pains as a probable outcome.

Another tissue that is often associated with the injuries of athletes isthe anterior cruciate ligament (ACL), the primary and most importantstabiliser of the knee. To continue with certain sports after havinginjured the cruciate ligaments is often associated with higher risks forskeleton damages.

Already in the 1960-ties were attempts done to replace injured ligamentswith artificial implants. The materials used for the artificialligaments were for instance polytetrafluor ethylene, polyethyleneterephtalate, polypropylene, polyethylene and carbon fibers.

Unfortunately, these early implants exhibited a number of drawbacks.Among other things, irreversible elongation and rupture of the implantstook place. Young's modulus for the above mentioned materials is oftentoo high for the materials to function well as implants that are areplacement for the anterior cruciate ligament.

In addition, it was desired to have a material in the implant that wasbiocompatible and biodegradable in that sense that it stimulated growthin the injured tissue while itself degraded. Thus, making the injuredtissue re-growth and taking over the bodily function as the implantdeteriorated. The above mentioned materials did not fulfil thiscriteria.

In SE, 505 703, C2, a material for use in implants disclosed, that isbiocompatible and biodegradable. The material disclosed is a linearblock polymer comprising urea and urethane groups, which polymerexhibits a molecular weight of at least 10⁴ Dalton.

While an implant comprising the described material has functionedsatisfactorily, there are numerous biological and mechanical parametersthat are to be fulfilled by a material for use in a biodegradableimplant.

High initial strength of the implant is required to prevent rupture ofthe implant before the bodily tissue has been able to re-growth and takeover the bodily function. A stepwise degradation of the material isessential to induce re-growth of the bodily tissue. Degradation speedshould be balanced to get optimum re-growth of tissue. The mechanicalproperties of the implant should be corresponding to that of the bodilytissue it is replacing so as to achieve as normal bodily function aspossible during healing.

Thus, there still exists a need to optimise the mechanical propertiesand the degradation speed for a material suitable for use in an implant.

DISCLOSURE OF INVENTION

The above problems are solved by the present invention through themanufacturing of a linear block polymer according to Formula (1):

wherein

-   -   R1 is derived from a diamine, e.g. ethylene diamine, 1,2-diamino        propane or 1,3-diamino propane;    -   R2 is derived from an aromatic diisocyanate;    -   R3 is derived from an esterdiol;    -   R4 is derived from dibutyl amine or ethanolamine;    -   Where 0<y<4 and z>8,        the monomers from which R2 and R3 are derived from are added in        such amounts that the molar ratio between R2 and R3 is larger        than 2:1. That is, the number of molars of monomer added that R2        is derived from, is more than twice the number of molars of        monomer added that R3 is derived from. As described in the        examples below, more than twice the amount of isocyanate to that        of esterdiol is added during the polymerisation process.

Through the present invention, a polymer is obtained that is moreoptimised as regarding the mechanical and degradation propertiescompared to that of prior art. The material obtained through the presentinvention can be made stiffer. It is also rendered a lower speed ofdegradation. That is, degradation is slower. In other words, thestrength of the material decreases slower than would be the case forconventional materials. How fast or slow the degradation goes, dependson the monomers chosen as staring materials.

According to one embodiment of the invention, R1 is derived fromethylene diamine, 1,3-diamino propane, 1,2-diamino propane, 1,4-diaminobutane, 1,5-diamino pentane, or 1,6-diamino hexane.

According to one embodiment of the invention, R2 is derived from4,4′diphenyl methane diisocyanate, naphthalene diisocyanate, or toluenediisocyanate.

According to one embodiment of the -invention, R3 is derived frompolycaprolactone diol, polydiethylene glycol adipate or poly (pentanediolpimelate).

The different monomers chosen for as R1 and R2 may be freely combinedwithin the realms of the invention.

According to the invention, the linear block polymer may be spun into afibre. The fibres may be produced by a wet spinning process described in“Gisselfält, K.; Flodin, P. Macromol. Symp. 1988, 130, 103-111”.

Preferably, the fibres produced from the linear block polymer describedabove exhibits a specific strength of at least 0.1 N/Tex, morepreferably above 0.2 N/Tex. The fibres exhibit high stiffness. Due tothat fact, an implant made from the fibres may obtain a stiffness thatmakes the implant work very well as a replacement for the injured bodilytissue. For some implants, it is desirable that the elongation at breakis not too high. Conventional polyurethane fibres of Spandex type, suchas Lycra, often exhibit too high elongation at break. A fibre producedfrom the linear block polymer according to the invention preferablyexhibits an elongation at break that is below 100%.

The linear block polymer according to the invention may be used indifferent forms, depending on the use. Examples of suitable forms arefibres, foams and films. Other examples are porous films or porouspolymeric material. Porous films are described in Swedish patent No. SE,C2, 514 064, which is hereby incorporated in its entirety. Further,porous film materials are described in Swedish patent application No.SE, A, 0004856-1, which is hereby incorporated in its entirety. SE, A,0004856-1 describes a method for manufacturing an open porous polymericmaterial.

The invention further concerns an implant for the implantation into thehuman or animal body, which implant comprises a linear block polymeraccording to the invention.

EXAMPLES Example 1

200 g (0.8 mol) 4,4′-diphenylmetandiisocyanate (MDI) was weighed in aflange flask. Nitrogen gas was applied and the MDI was slowly melted at50° C. 202 g (0.38 mol) polycaprolacton diol (PCL) was weighed in a dropfunnel and added during slow stirring, drop by drop, to the melted MDI.T=50-60° C.

24.6 g of the obtained prepolymer was dissolved under nitrogen gas inabout 127.6 ml dimethyl formamid. 1.84 g (24.8 mmol) 1,3-diamino propaneand 0.13 g (1.0 mmol) diamino butane was weighed in a beaker and added,together with 38.3 ml DMF, to the dissolved prepolymer during heavystirring. A clear, viscous solution was obtained within seconds.M_(peak)=102 000 g/mol compared to PEO in DMF+0.5% LiCl.

Example 2

A prepolymer was manufactured according to Example 1, but with themodification that 1075.9 g (2.03 mol) PCL was mixed with 1035.2 g (4.14mol) MDI. 20.34 g of the obtained prepolymer was dissolved undernitrogen gas in 84.3 ml dimethyl formamide (DMF). In the chain extensionstep 19.8 mmol 1,3-diamino propane, 0.51 mmol diamino butane and 21.1 mlDMF, was used. A clear, viscous solution was obtained within seconds.M_(peak)=106 000 g/mol compared to PEO in DMF+0.5% LiCl.

Example 3

23.94 g prepolymer from Example 2 was dissolved in 101.7 ml DMF. In thechain extension step, 23.8 mmol 1,5-diamino pentane, 0.9 mmol diaminobutane and 25.5 ml DMF was used. A clear, viscous solution was obtainedwithin seconds. M_(peak)=106 000 g/mol compared to PEO in DMF+0.5% LiCl.

Example 4

A prepolymer was manufactured according to Example 1, with themodification that 1048.7 g (1.98 mol) PCL was mixed with 1041.2 g (4.06mol) MDI. 18.96 g of the thus obtained prepolymer was dissolved undernitrogen gas in 68.2 ml dimethyl formamide (DMF). In the chain extensionstep 17.7 mmol 1,2-diamino propane, 3.1 mmol diamino butane and 29 ml ofDMF, was used. A clear, viscous solution was obtained within seconds.M_(peak)=25 000 g/mol compared to PEO in DMF+0.5% LiCl.

Example 5

27.18 g of the prepolymer obtained according to Example 1 was dissolvedunder nitrogen gas in 104 ml dimethyl formamide-(DMF) and 1.23 g MDI wasadded. In the chain extension step 31.9 mmol 1,3-diamino propane, 1.3mmol diamino butane and 44.6 ml DMF was used. A clear, viscous solutionwas obtained within seconds. M_(peak)=86 000 g/mol compared to PEO inDMF+0.5% LiCl.

Measurements of Molecular Weight

The molecular weight of the polymers obtained from the above exampleswere measured by Size Exclusion Chromatography (SEC), with a Waters 2690Separations Module provided with a Waters 996 Photodiode Array Detectorand a Waters 2410 Refracive Index Detector. Two Styragel colons, HT6Eand HT3, were run consecutively with a flow rate of 1 ml/minute ofdimethyl formamide (DMF) comprising 0.005 g LiCl/l. The retention timewas transformed into average molar mass (M_(peak)), with the use ofpolyethylene oxide as a standard.

Fibre Spinning

In short, the fibre spinning process comprises the steps of: thepolymeric solution being extruded through a spinneret into a coagulationbath containing warm water; in a second water bath, the fibre isstretched; the fibre is rolled up on a spool, which is allowed to dry.

The Mechanical Properties of the Fibre

The mechanical properties of the spun fibre were measured. The result isshown in the table below. Solvent Specific spinning strength Stiffness ×10³ Elongation Polymer. bath (N/Tex) (N/mm) at break (%) Example 1 DMF0.25 ± 0.015 50 ± 3 29 ± 4 Example 2 DMF 0.28 ± 0.01  62 ± 4 40 ± 3Example 3 DMF + LiCl 0.16 ± 0.015 56 ± 3  28 ± 10Degradation Tests

Controlled degradation of the polymer in a pace that enables repairand/or in-growth of bodily tissue are of great importance. Thedegradation circumstances for the linear block polymer of the inventionwas studied as buffered phosphate solution having a pH of 7.4. Thetemperature was kept at 77° C. During the degradation time, themechanical properties of the polymer was measured.

FURTHER DESCRIPTION OF THE INVENTION

In the present study we describe the synthesis, wet-spinning, mechanicaltesting and degradation of poly(urethane urea)s (PUUR) intended forclinical use in anterior cruciate ligament (ACL) reconstruction. Theeffects of soft segment chemical composition and molar mass, and thekind of diamine chain extender on the material properties wereinvestigated. It was found that the fibres made of PUUR withpolycaprolactone diol (PCL530) as soft segment and MDI/1,3-DAP as hardsegment, (PCL530-3), have high tensile strength and high modulus, andwhen degraded keep their tensile strength for the time demanded for theapplication. In conclusion, from a chemical and mechanical point of viewPUUR fibres of PCL530-3, ARTELON™, are suitable for designing adegradable ACL device.

Introduction

Ligament injuries in the knee joint are among the most common sportinginjuries.^(1,2) Ruptures of the anterior cruciate ligament (ACL), theprimary and most important stabiliser of the knee,³ are the most commonserious ligament injuries. In the 1960s the first ACL reconstructionswith synthetic materials were performed.⁴ The introduction of ligamentprostheses generated much interest because it offered the benefit ofquick recovery and rapid rehabilitation.⁵ While early results werepromising, the long-term results were disappointing. A number ofproblems were reported, including irreversible elongation, rupture andformation of wear debris.

Materials used for these prosthetic devices or reinforcement ligamentbands were e.g. poly(tetrafluoroethylene), poly(ethyleneterephtalate),^(1,4,6-9) polypropylene, polyethylene, carbon fibres¹⁰and polydioxanone.¹¹ The common properties of these materials are a toohigh elastic modulus compared to native ACL and permanent deformationafter repeated loading due to non-elastic behaviour.

Materials with elastic behaviour and modulus above rubber level can befound among the multiblock copolymers. Poly(urethane urea)s (PUUR) aremultiblock copolymers, which combine excellent mechanical propertieswith documented blood compatibility.^(12,13) These properties havefavoured the use and development of PUUR as biomaterials, particularlyas products for blood applications.¹⁴⁻¹⁷

PUURs are made of soft segments based on polyether or polyester and hardsegments based on the reaction of diisocyanate and diamine chainextender. Due to the thermodynamic incompatibility between the twosegments, PUURs undergo micro-phase separation resulting in thephase-separated heterogeneous structure that can be considered as hardsegment domains dispersed in a soft segment matrix. The various physicalproperties of the material such as strength, modulus, and elasticity areclosely correlated with the domain structure and the interaction betweenthe segments inside the domain. By adjusting the chemical nature andrespective amounts of reagents, it is possible to obtain a wide range ofmaterials with different properties. Thus, materials may be tailored forvarious applications.

In designing a degradable device for anterior cruciate ligament (ACL)reconstruction, whether a true prosthesis or an augmentation device,many biological and mechanical criteria must be met. High initialstrength is needed to prevent mechanical failure of the implant prior totissue ingrowth.¹⁸ In addition, a moderate degradation rate is requiredto induce ingrowth of organized tissue.¹⁹ If degradation is too rapid,the host tissue may be exposed to stresses that are too great, resultingin failure. On the other hand, if the degradation is too slow, stressshielding may occur.¹⁹ Thus, a new material for ACL reconstructionshould be 1) Compatible with surrounding tissues and allow cell ingrowth2) Intended to be mechanically similar to native ACL 3) Degradable,but-keeping at least 50% of its strength and stiffness for at least 9-12months. A possible way to fulfil these requirements is to use a textilecomposition made of degradable PUUR fibres. Thus, the aim was to makePUUR fibres suitable for designing a degradable ACL device. Previouslymade PUUR fibres of the Spandex type, e.g. Lycra, are unsatisfactory foruse as ligaments. In particular, their elastic modulus is too low andthey are not degradable.

In this paper the synthesis, wet spinning, mechanical properties anddegradation of a number of PUUR fibres are presented. The effects ofsoft segment chemical composition and content and the kind of diaminechain extender on the material properties are investigated.

Experimental Section

Materials. Polycaprolactone diols (PCL) ({overscore (M)}_(n)=530 g/mol)and ({overscore (M)}_(n)=1250, 2000 g/mol) were obtained from Solvay andAldrich, respectively. Adipic acid, di(ethylene glycol),di-n-butylamine, ethylene diamine (EDA), 1,2-diaminopropane (1,2-DAP),1,3-diaminopropane (1,3-DAP), 1,4-diaminobutane (1,4-DAB),1,5-diaminopentane (1,5-DAPe), 1,6-diaminohexane (1,6-DAH) and lithiumchloride (LiCl) were purchased from Fluka. 4,4′-diphenylmethanediisocyanate (MDI) was provided by Bayer AB. N,N-dimethylformamide (DMF)99.8% and toluene 99.8% were obtained from Labscan.

Polyester synthesis. Hydroxytelechelic polyesters were synthesized fromadipic acid and di(ethylene glycol) with acid catalyst until the acidnumber was <2 as determined by titration of aliquots with 0.1 molar KOHin ethanol. The removal of water to drive the reaction at a reasonablerate was achieved by azeotropic distillation with toluene. Threeproducts with hydroxyl numbers of 56 ({overscore (M)}_(n)=2000 g/mol),112 ({overscore (M)}_(A)=1000 g/mol) and 223 ({overscore (M)}_(n)=500g/mol), respectively, as determined according to ASTM D 4274-94, wereused in the present study.

Polymerization. PUURs²⁰ were synthesized by a two-step method describedearlier.²¹ In the first step a prepolymer was formed. The polyester diolwas added slowly to 4,4′-diphenylmethane diisocyanate (MDI)(NCO:OH=2.05:1) in bulk at 50° C. in a dry N₂ atmosphere. The isocyanatecontent was determined by reacting the prepolymer with an excess ofdi-n-butylamine in toluene. After the reaction was complete, the excessdi-n-butylamine was determined by back titration with standardhydrochloric acid.

In the second step a dilute solution of diamine chain extender andmonoamine chain stopper in DMF was added rapidly to a solution ofprepolymer in DMF (20 wt.-%) under intense stirring at 20° C. The molarratio NCO:NH₂ was 1:1 with 2% monoamine. The final polymer content was18 wt.-% . The chemical compositions of the various PUUR can be seen inTable 1.

Fibre spinning. Fibres were prepared by a wet spinning process²¹(equipment from Bradford University Research Limited, Bradford,England). The polymer solution was metered through a spinneret (120holes, Ø80 μm) submersed in a coagulating bath containing water. In asecond water bath the fibre bundle was drawn after which themultifilament fibre was taken up on a spool. The temperature in thewater baths was varied from 20 to 80° C. to get as high draw ratio aspossible. The spools with fibres were rinsed in running tap waterovernight and dried at room temperature. For each batch of fibres lineardensity, tensile strength, stiffness and elongation at break weredetermined.

Band production. The wet spun multifilament fibres were by doubling andslight twisting converted to a coarse yarn, which was used as warpthreads. The bands were woven on a narrow fabric needle loom (typeFX2/65, Mageba Textilmaschinen Vertriebs GMBH, Germany) with low wefttension in plain weave to utilise as much as possible of the yarnstrength combined with good stability.

Density measurements. The density of the fibres was measured with aMicrometrics Multivolume Pycnometer 1305.

Porosity measurements. Pore sizes and pore size distributions of thewoven bands were measured by mercury porosimetry, Micromeretics AutoPoreIII 9410.

Polymer degradation. Samples of fibres and bands were placed in vials ina great surplus of 0.06 M phosphate buffer solution pH 7.4 (Na₂HPO₄ andKH₂PO₄.²² The sealed vials were placed in thermostat ovens at 37° C. and77° C. At intervals the vials were opened and aliquots of material weretaken out. Changes in molar mass and loss of tensile strength wereinvestigated.

Size Exclusion Chromatography (SEC). Size Exclusion Chromatography (SEC)was conducted with a Waters 2690 Separations Module equipped with aWaters 996 Photodiode Array Detector and a Waters 2410 Refractive IndexDetector. Two Styragel columns, HT6E and HT3, were operated in series ata flow rate of 1 ml/min in DMF containing 0.5% (w/v) LiCl to preventaggregation. The retention times were converted to apparent molar massesusing poly(ethylene oxide) standards.

Linear density measurements. The linear density of the fibres wasdetermined by weighing of a known length of fibre, typical 100 m, and ispresented in tex. The tex unit is defined as g/1000 m.

Mechanical testing. After equilibration with water at 20° C. for 30minutes, the multifilament fibres and the woven bands were tested in thewet state in a tensile tester (UT 350/5 LS Universal Testing machine SDLInternational Ltd. Stockport). The constant rate of extension was 900mm/minute and the sample lengths were 100 mm for fibres and 30 mm forthe woven bands.

Differential Scanning Calorimetry (DSC). Thermal analysis was carriedout on a Perkin-Elmer Pyris1. The heating rate was 10° C./min over atemperature range of −100 to 150° C. The sample was cooled to −100° C.and then a second run was performed. Glass transition temperatures weredetermined from the second scan.

Results and Discussion

Polymerization. In a first study, PUURs were synthesized usingpoly(di(ethylene glycol) adipate) (PDEA) or polycaprolactone diol (PCL),with different molar masses as soft segments, MDI and EDA as chainextender (Table 1). The length of the soft segment was altered bychanging the molar mass of the polyesterdiol while the length of thehard block was unchanged. However, there was a distribution of hardblock lengths as a consequence of the stoichiometric ratio in theprepolymerization step.²³ As the soft segment was shortened from 2000g/mol to 500 g/mol the hard block content increased from 23% by weightto 55%. An immediate effect was that the solubility in DMF decreasedwith increasing hard block content, resulting in turbidity and gelationa few minutes after chain extension.

Another series of PUURs was prepared using PCL530 as soft segment, MDIand six different aliphatic diamines as chain extenders (Table 1). TABLE1 Composition and solubility of PUURs. Chain Soft segment Hard block DMFsolution Sample code extender M_(n) content (%) (18%, 22° C.) M_(peak) ×10^(−3c) PDEA2000-2 EDA 2000 23.0 Opaque^(a) 86 PDEA1000-2 EDA 1000 37.7Opaque 86 PDEA500-2 EDA 500 55.9 Opaque 115 PCL2000-2 EDA 2000 23.0Opaque 105 PCL1250-2 EDA 1250 33.0 Opaque 121 PCL530-2 EDA 530 51.4Opaque 125 PCL530-2Me 1,2-DAP 530 52.0 Clear^(b) 106 PCL530-3 1,3-DAP530 52.0 Clear 125 PCL530-4 1,4-DAB 530 53.0 Opaque 123 PCL530-51,5-DAPe 530 53.6 Opaque 106 PCL530-6 1,6-DAH 530 54.2 Opaque 106^(a)Opaque: hazy, poorly solubilized in the above condition.^(b)Clear: transparent, absolutely solubilized in the above condition.^(c)Poly(ethylene oxide) equivalent M_(peak).

The different chain extender structures affected the solubility of thepolymer in DMF. These PUURs have almost the same hard/soft ratio andshowed solubility in the order1,2-DAP>1,3-DAP>1,5-DAPe>1,6-DAH>1,4-DAB>EDA. In the reactions alldiamines but 1,2- and 1,3-DAP gave rise to turbid solutions 5-20 minutesafter chain extension. After still some time brittle gels were formed.1,3-DAP formed clear polymer solutions, but they were turbid and gelledafter a few days. PCL530-2Me solutions remained clear for at least oneyear. This is the most apparent difference between 1,2-DAP and the otherfive chain extenders and is explained in terms of less efficienthydrogen bonding due to steric effects from the pendant methyl group.Similar behaviour has been seen for PUUR systems chain extended witharomatic diamines with substituents that increased the steric effects.²⁴

The lower solubilities of the other PUURs probably depend on theinfluence of the urea structure on the association behaviour. PUURsolutions with even number of methylene groups in the chain extender gotturbid very soon while odd numbered remained clear for longer times.Similar results were found by Joel et al.,²⁵ who studied steric odd-eveneffects of various urea structures of PUUR on solution properties inDMF. They found that the viscosity of solutions with odd number ofmethylene groups was independent of time, while the even numbered onesshowed turbidity and a drastic increase in viscosity with time followedby gelation. The turbidity was explained by formation of a higherconcentration of physical crosslinks caused by hydrogen bonding withinthe hard block domains.²⁶ The solution process becomes restricted if thehard segment domains are perfectly arranged and form a physicallycrosslinked network. Thus, the good solubility of PCL530-3 may beexplained by a lower degree of hydrogen bonding compared to the otherchain extenders.

A requirement for spinnability is that the polymer is soluble. Thesolvent, DMF, should prevent gelation due to hard segment interactionbefore spinning, but the solubility of PUUR in DMF is poor. By addingLiCl (0.07 g LiCl/g polymer solution) to the polymer solutions turbiditycould be removed and gelation could be prevented.²⁵ The increasedsolubility is based on the destruction of the hydrogen bonds betweenchains and on a simultaneous blocking of the acceptor positions owing tothe favoured complex formation between Li and carbonyl oxygen.²⁷

Fibre spinning. The fibres are formed in a wet spinning process. In thefirst step precipitation occurs and the solvent diffuses out of theextrudate into the bath, and non-solvent diffuses from the bath into theextrudate. The rate of the coagulation has a profound effect on the yarnproperties. Important process variables are for example concentrationand temperature of the spinning solution, composition and temperature ofthe coagulation bath.

The temperature of the spinning solutions was kept within 20-25° C. andthe polymer concentration was 18 wt.-%. No correlation between polymercontent and tensile properties could be seen. However, a spinningsolution viscosity of more than 1 Pas was needed to be able to get astable spinning process.

The temperature of the coagulation bath was found to be of greatimportance. The rate of PUUR coagulation occurring when the polymersolution was extruded into the water depends on the coagulationtemperature and influences both the morphology of the undrawn fibre andthe ultimate fibre properties. The suitable spin bath temperature forPDEA based PUURs was about 20° C. (Table 2). At higher temperatures thepolymer got stuck in the spinneret. In contrast the PCL based PUURsseemed to be easier to spin the higher the temperature (Table 2). Thisdifference between the two polyesters can be due to their difference inhydrophilicity²⁸.

In the second water bath the fibre bundle is drawn to get molecularchain orientation and thereby improve the mechanical properties. Thehigher the draw ratio, the lower the elongation and the stiffer andstronger the fibre.

The effect of draw ratio on tensile properties for PCL530-3 is seen inFIG. 1.

TABLE 2 Spin parameters for different PUURs Sample Spin T_(draw optimal)^(a) Draw ratio_(20° C.)/ Draw code solvent (° C.) Drawratio_(Tdraw optimal) ratio PDEA2000-2 DMF + 20 — 5 LiCl PDEA1000-2DMF + 20 — 5 LiCl PDEA500-2 DMF + 20 — 4.5 LiCl PCL2000-2 DMF + 60 0.586 LiCl PCL1250-2 DMF + 60 0.57 6 LiCl PCL530-2 DMF + 60 0.72 5PCL530-2Me DMF 60 0.67 9 PCL530-3 DMF 60 0.72 5.4 PCL530-3 DMF + 80 0.445.4 LiCl PCL530-4 DMF + 80 0.70 5.4 LiCl PCL530-5 DMF + 80 0.46 6.4 LiClPCL530-6 DMF + 80 0.54 7.4 LiCl^(a)T_(draw optimal) = the temperature at which the highest draw ratiois achieved

The draw ratio of the fibres is dependent on the temperature not only inthe coagulation bath but also in the stretching bath. It was found thatthe best processability and draw ratio were achieved when the baths hadthe same temperature. The spinning conditions are shown in Table 2.Three different groups are identified. The first group contains PDEAbased PUURs, described earlier, which have best processability and drawratio at 20° C. The second group contains PCL based PUURs chain extendedwith EDA spun from DMF+LiCl, and PCL530-2 Me and PCL 530-3 spun fromDMF. These obtain their highest draw ratio at 60° C. and theirdrawability is directly proportional to the temperature. In the thirdgroup the highest draw ratio is achieved at 80° C., maybe it is possibleto increase their draw ratio further if the temperature is raisedfurther. This group contains PCL-based PUUR with chain extenders withmore than two methylene groups and are spun from DMF+LiCl. Even thoughthe highest draw ratio was achieved at the same temperature within eachgroup, the temperature dependence of draw ratio of the fibres differed(Table 2 and FIGS. 2a, b).

The increase in draw ratio of PCL530-5 was almost proportional to thetemperature, while the increase in draw ratio of PCL530-3 showed weaktemperature dependence between 20° C. and 50° C. Above that interval thedrawability was directly proportional to the temperature. Thedrawability of PCL530-4 and PCL530-6 was constant at temperatures below60° C. and 70° C., respectively. At these temperatures strongtemperature dependence in drawability appeared. Additionalinvestigations are needed to explain these differences.

Band production. The appropriate force at break of the finished andsterilised band should be 1200 N. Based on practical experiences thetheoretical breaking force therefore was chosen to 1600 N in order tocalculate the resulting cross section of the band as well as the numberof fibres needed. Furthermore the diameter of the band was not allowedto exceed 5±1 mm. In the finished band three circular yarns are placedin a triangular form. Assuming hexagonal close packing of the fibres inthe yarn,²⁹ the yarn radius can be calculated. From the calculations itis given that the tenacity of the fibres should be at least 0.2 N/tex tomeet the criteria of strength and size.

Porosity measurements. In medical applications the pore sizes and theirdistributions are of great importance for promoting cell ingrowth. Themultifilament fibres made from wet spinning have a high void content.Furthermore, when fibres are processed into woven structures, varyingdegrees of porosity can be provided. The pore sizes and pore sizedistribution of two woven bands made of 1500 multifilament PCL530-3fibres are presented in Table 3. The smallest pores, <8 μm, is probablybetween the filaments in the multifilament fibre while pores between 8μm and 600 is the space between the fibres in the warp and weft (FIG.3). Almost half of pores (49%) are 21-100 μm, sizes that may be suitablefor fibrous connective tissue ingrowth.³⁰ About 20% of the pores are100-400 μm, pore sizes, which have been shown to be suitable forosteoblast ingrowth in hard tissue applications.³¹ TABLE 3 Pore sizesand pore size distributions of PUUR bands. Interval (μm) Pores (%)401-600 6.8 201-400 15.6 101-200 8.0  51-100 20.7 21-50 28.3  8-20 10.71.0-7.9 4.5 <1 5.4

Mechanical testing. The tensile properties of the fibres are shown inTable 4. In the first series the length and composition of the esterdiolwas varied and the hard block was formed from MDI and EDA. The effectsupon shortening the soft segment were seen in increased stiffness anddecreased elongation of the fibres. The largest effect is seen whencomparing polymers made from soft segments of molar masses of ˜1000g/mol and ˜500 g/mol. As a consequence of the shortening of the softsegment the hard/soft ratio increases. The hard blocks, which areextensively hydrogen bonded, mainly affect the stiffness and serve asboth cross-links and filler particles in the soft segment matrix. It isknown that the strength and modulus of polyurethane copolymers aredirectly related to the amount and stability of the hard segmentdomains.³² Wang and Cooper³² studied the effect of the hard blockcontent and block length on the morphology and properties of PUURssystematically. They found that the mechanical properties dependedprimarily on the hard block content and the strong hard-domain cohesiondue to interurea hydrogen bonding that resulted in semicrystallinebehaviour.

The effects on the mechanical properties of the PCL 530 based PUURfibres chain extended with six different aliphatic diamines wereinvestigated (Table 4). The hard segment content is almost constant, buttheir structures differ. The strongest fibres were obtained fromPCL530-2Me and PCL530-3, which are supposed to be less efficientlyhydrogen bonded in solution compared to the other PUURs. PCL530-2Me andPCL530-3 formed clear solutions and could be spun without addition ofLiCl. As LiCl was added to a PCL530-3 solution the tenacity of the fibreproduced thereof decreased more than 40%. Nevertheless, the tenacity ofPCL530-3 fibre from DMF+LiCl was still among the highest. Upon acomparison of fibres spun from DMF+LiCl solutions PCL530-3 and PCL530-5are the strongest. Thus, chain extenders with an odd number of methylenegroups tend to form stronger fibres than those with even numbers. Fromthe design of the ACL reconstruction band it was given that the fibreshould have a tenacity of at least 0.2 N/tex. Only two of the testedfibres, made from PCL530-3 and PCL530-2Me, met this requirement. TABLE 4Mechanical properties of different PUUR fibres. Sample Spin TenacityStiffness × 10³ Elongation code solvent (N/tex)^(a) (N/mm) at break (%)PDEA2000-2 DMF 0.06 ± 0.004   6 ± 0.5 130 ± 13 PDEA1000-2 DMF 0.06 ±0.004   6 ± 0.4 120 ± 10 PDEA500-2 DMF + 0.08 ± 0.005 17 ± 1 50 ± 5 LiClPCL2000-2 DMF + 0.13 ± 0.007   6 ± 0.3  77 ± 12 LiCl PCL1250-2 DMF +0.11 ± 0.005   6 ± 0.4  74 ± 14 LiCl PCL530-2 DMF + 0.10 ± 0.01  45 ± 232 ± 8 LiCl PCL530-2Me DMF 0.25 ± 0.015 50 ± 3 29 ± 4 PCL530-3 DMF 0.28± 0.01  62 ± 4 40 ± 3 PCL530-3 DMF + 0.16 ± 0.008 50 ± 3 34 ± 2 LiClPCL530-4 DMF + 0.10 ± 0.01  60 ± 3 25 ± 3 LiCl PCL530-5 DMF + 0.16 ±0.015 56 ± 3  28 ± 10 LiCl PCL530-6 DMF + 0.11 ± 0.01  70 ± 3 16 ± 5LiCl^(a)Density of fibres = 1.23 g/cm³

Bands. Typical tensile test diagram of a band of PCL 530-3 fibres isgiven in FIG. 4. The shape of load-elongation curve of the band issimilar to that of the fibre, but the elongation is higher. This isexpected as the fibres are slightly twisted to get a coarse yarn beforeweaving.

Differential Scanning Calorimetry. The glass transition temperatures ofthe soft blocks for the different PUURs are presented in Table 5. As themolar mass of the soft segments decreased the T_(g) increased from −30.7to −5.5° C. and from −48.3 to −11.3° C. for PDEA and PCL respectively.The T_(g) was harder to detect the shorter the soft segment. The effectof soft segment length on its T_(g) is related to the limitation of thesoft segment mobility imposed by the attached hard segment. Beside themolar mass of the soft segment, the chain extender affected the T_(g) sosome extent. PCL530-2Me and PCL530-3 showed the highest T_(g). For chainextenders with three or more methylene groups there was a movementtowards higher T_(g) the longer the diamine. All PUUR fibres butPCL530-2Me and PCL530-3 were spun from DMF+LiCl. PCL530-3 spun fromDMF+LiCl showed no change in T_(g) compared to PCL530-3 spun from DMF.The phase mixing of soft and hard segments makes thermal molecularmotion in soft segment phase restricted. Therefore, the shifts of T_(g)to higher temperatures are attributed to the interaction between hardand soft segments. TABLE 5 DSC data Soft segment Sample code T_(g) (°C.) PDEA2000-2 −30.7 PDEA1000-2 −25.7 PDEA500-2 −5.5 PCL2000-2 −48.2PCL1250-2 −39.1 PCL530-2 −11.3 PCL530-2Me −9.2 PCL530-3 −8.4 PCL530-3(LiCl) −8.3 PCL530-4 −10.2 PCL530-5 −11.2 PCL530-6 −13.7

Degradation studies. Among the various bonds present in PUUR, the mostsusceptible ones are the ester bonds of the soft segments which uponhydrolysis yield carboxylate and hydroxyl groups. The acid produced cancatalyse the ester hydrolysis so that an autocatalytic reaction becomesprevalent. Furthermore, the intended use for the material is in the kneethat has a neutral pH.³³ For that reason all degradation studies werecarried out in a great surplus of buffered solutions at pH 7.4. Bothchanges in molar mass and tensile strength of optimal drawn fibres andbands thereof were studied. The data for fibres and bands obey the samedependence on change in molar mass and tensile strength. Thus, thedifference in fibre packing and sample thickness do not seem to have anyeffect on degradation rate.

The loss in tensile strength with hydrolysis time at 77° C. is shown inFIG. 5.

For both PDEA- and PCL-based PUUR the polymer with longer soft segmentsdegraded faster. Thus, PDEA2000 and PCL2000 display lower hydrolyticallystability than PCL530 and PDEA500, respectively. The reason is a higherfraction of soft segments and, consequently, of ester groups exposed tohydrolysis.

The chemical composition of the ester affects the degradation rate ofthe different PUURs. PUURs with soft segments made of PDEA degradefaster than those based on PCL. The superior resistance to hydrolysis isascribed to the hydrophobicity of PCL. It has been shown that theintroduction of hydrophilic poly(oxyethylene) blocks in PCL-POE-PCLtriblock copolymers did increase the hydrophilicity and degradation ratecompared with the homopolyester PCL²⁸. PDEA 500 contains about threediethylene glycols whereas the PCL diols initiated with diethyleneglycol contain one.

The initial molar mass of the different PUURs varied to a small extent(Table 1). The rate of the decrease in tensile strength was notaffected, but the time to complete degradation became somewhat shorterthe lower the initial molar mass. The molar mass decreases after aninduction period of about 10 days for PCL530-2 and -3 and about 3 daysfor PCL1250-2 (FIG. 6). No induction period was seen for the othersamples. During the induction period a decrease in SEC retention timewas seen. The phenomenon has been occasionally reported by someresearchers using both in vitro and in vivo systems,^(34,36) but nounanimous conclusions on the reasons for the increase were drawn. Wehave interpreted the decrease in retention time, as aggregation of thepolymer due to a physical process since no unreacted isocyanate groupsis present in the polymers. Furthermore, in spite of the increase inmolecular size the tensile strength decreased already after 2 days inphosphate buffer (FIG. 5).

One of the requirements of the material was that at least 50% of thetensile strength should be kept for at least 9-12 months. For use atbody temperature it is interesting to estimate and investigate theconformity between the degradation rate at 37° C. and 77° C.

Since fibres of PCL530-3 seem to have the most promising properties frommany aspects further degradation studies at 37° C. were made thesefibres. The change in molar mass at 37° C. follows the same pattern asat 77° C. After about 40 days a decrease in SEC retention time for thepolymer is seen, which is similar to the results after 2-3 days at 77°C. After that the retention time is constant for a long period of time.This means that the size of the formed aggregates is to some extentindependent of the molar mass of the molecules that take part in theaggregate formation. It is obvious that the degradation proceeds sinceafter 500 days the SEC retention time has increased accompanied by a theloss in tensile strength of 5-10%. Thus, the degradation rate at 37° C.seems to be about 1/20 lower than of the degradation rate at 77° C.

In addition to loss of tensile strength and molar mass, the mass changeof the PCL530-3 fibres has been studied. First the mass of the fibresincreased about 8-10% due to water adsorption. After 52 days at 77° C.there were signs of mass loss and after another ten days the mass lossis obvious (−30%). At that time the fibres were very brittle at andfurther measurements were hard to perform. In accordance with the lowdegradation rate at 37° C. it is not expected to see any decrease in themass before 800-850 days of degradation.

Regarding the biocompatibility of the PCL530-3 both safety studies,mutagenicity and delayed contact hypersensitivity, and implantationstudies have been performed and reported.³⁷ When PUUR bands made ofPCL530-3 fibres were used as ACL prosthesis in rabbits and minipigs,bone formation was seen in the drilled tunnels and surrounding the PUURfibres. Also, irrespective of observation time, connective tissue ingrowth was observed between and in close contact with the PUUR fibres inboth species. At observation times exceeding 6 months, the connectivetissue had an orientation of the collagen fibres and fibroblasts inparallel with the PUUR fibers.³⁷ From clinical trials using the PUURband as an ACL augmentation, biopsies were obtained from 5 patients attimes between 30 to 40 months. As in the animals a high percentage ofconnective tissue ingrowth was found in close contact with the materialand the presence of collagen type I and blood vessels was confirmedusing immunohistochemical methods. No indications of obviousinflammatory reaction or foreign body response were detected.

Conclusions. We have demonstrated that the chemical composition of PUURcan be tailored to get fibres with strength, stiffness and degradationrate, which fulfil the desired properties of a material for ACLreconstruction.

Fibres made of PUUR based on PCL 530 have superior strength andstiffness compared to other polyesterdiols used in the study and keep atleast 50 percent of its original tensile strength more than nine monthsat body temperature. Furthermore, chain extension of PCL530:MDI with1,3-DAP produces a polymer solution from which strong fibres can be spunwithout additives. A porous band with appropriate strength and size canbe woven of the fibres.

In conclusion, from a chemical and mechanical point of view fibres ofPCL530-3, ARTELON™, are suitable for designing a degradable ACL device.Human clinical trials with ACL reconstruction using the PUUR band are inprogress.

Acknowledgement. The Knowledge Foundation via the Material ResearchSchool at Chalmers University of Technology is gratefully acknowledgedfor financial support.

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1. Linear block polymer according to Formula (1)

Wherein R1 is derived from a diamine, e.g. ethylene diamine, 1,2-diaminopropane or 1,3-diamino propane; R2 is derived from an aromaticdiisocyanate; R3 is derived from an esterdiol; R4 is derived fromdibutyl amine or ethanolamine; Where 0<y<4 and z>8, characterized inthat, the monomers from which R2 and R3 are derived from are added insuch amounts that the molar ratio between R2 and R3 is larger than 2:1.2. Linear block polymer according to claim 1, wherein R1 is derived fromethylene diamine, 1,3-diamino propane, 1,2-diamino propane, 1,4-diaminobutane, 1,5-diamino pentane, or 1,6-diamino hexane.
 3. Linear blockpolymer according to claim 1, wherein R3 is derived frompolycaprolactone diol, polydiethylene glycol adipate or poly(pentanediolpimelate).
 4. Linear block polymer according to claim 1, wherein R2is derived from 4,4′diphenyl methane diisocyanate, naphthalenediisocyanate, or toluene diisocyanate.
 5. Fibre manufactured from alinear block polymer according to claim
 1. 6. Fibre according to claim5, which fibre exhibits a toughness of at least 0.1 N/Tex.
 7. Fibreaccording to claim 6, which fibre exhibits a toughness above 0.2 N/Tex.8. Fibre according to claim 5 which fibre exhibits an elongation atbreak that is below 100%.
 9. Fibre according to claim 5 which fibreexhibits an elongation at break that is 43% or below.
 10. Filmmanufactured from a linear block polymer according to claim
 1. 11.Porous polymeric material manufactured from a linear block polymeraccording to claim
 1. 12. Implant for the implantation into the human oranimal body, which implant comprises a linear block polymer according toclaim
 1. 13. Linear block polymer according to claim 2, wherein R3 isderived from polycaprolactone diol, polydiethylene glycol adipate orpoly(pentane diolpimelate).
 14. Linear block polymer according to claim2, wherein R2 is derived from 4,4′diphenyl methane diisocyanate,naphthalene diisocyanate, or toluene diisocyanate.
 15. Linear blockpolymer according to claim 3, wherein R2 is derived from 4,4′diphenylmethane diisocyanate, naphthalene diisocyanate, or toluene diisocyanate.16. Fibre manufactured from a linear block polymer according to claim 2.17. Fibre manufactured from a linear block polymer according to claim 3.18. Fibre manufactured from a linear block polymer according to claim 4.19. Fibre according to claim 6 which fibre exhibits an elongation atbreak that is below 100%.
 20. Fibre according to claim 7 which fibreexhibits an elongation at break that is below 100%.